Dr. Valerie Knopik, a behavior geneticist with expertise in quantitative genetics, holds a faculty position in the Department of Psychiatry at Washington University School of Medicine. A Mentored Research Scientist Development Award (K01) is solicited, to support 5 years of research on the joint effects of prenatal nicotine exposure and genetic risk factors in the etiology of externalizing behaviors in children. If granted, this award will allow Dr. Knopik a period of intensive training in molecular genetics, behavioral and physiological effects of nicotine, maternal and child psychopathology assessments, and epidemiology, which will include coursework, laboratory work, clinical exposure, and research under the sponsorship of Dr. Andrew Heath, a renowned behavioral geneticist, and Dr. Richard Todd, a renowned child psychiatrist with expertise in molecular genetics. In addition to the evidence for genetic effects on ADHD (Attention-Deficit Hyperactivity Disorder) and conduct problems, there is suggestive evidence for a role of maternal smoking during pregnancy in the risk of offspring externalizing behaviors. To develop a more comprehensive model for the etiology of externalizing behavior, one must consider the joint effects of genotype and prenatal environment. The overall goal of the research plan is to assess genotype and prenatal nicotine effects on childhood externalizing behaviors using a combination of secondary data analyses and new pilot data collection. Most studies that have focused on prenatal exposure to nicotine have implemented statistical control for other potential risk factors, but since the range of potential confounding factors is unknown, such between-mother controls are likely to be imperfect. Using an innovative within-mother comparison that focuses on externalizing disorder outcomes in offspring of mothers discordant for smoking during pregnancy (i.e., full sibling pairs discordant for prenatal nicotine exposure), the new pilot data collection can overcome many of the limitations of previous research. Dr. Knopik's long-term goal is to become an independent investigator with a program of research on prenatal substance exposure and its role in the etiology of externalizing behavior and associated learning and cognitive deficits, and to identify genes (both maternal and offspring) that may affect childhood outcomes of maternal substance use during pregnancy.